ABSTRACT Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Current therapies afford clinical improvement, however, they are not curative and elicit significant side-effects. We discovered that the mechanistic target of rapamycin (mTOR) is activated in ?untouched? T cells, which precedes disease flares and underlies abnormal lineage specification in patients with SLE. mTOR is also activated and sirolimus blocks autoimmunity and any sign of disease in lupus-prone mice. Therefore, we initiated a prospective study of rapamycin (sirolimus by generic designation) in SLE patients unresponsive or intolerant to conventional medications. As primary clinical efficacy endpoint, SLEDAI and BILAG scores were progressively reduced over 12 months in 16/29 patients (55%). 19/29 patients (65.5%) met criteria for SLE Responder Index (SRI). Prednisone use was markedly diminished. Sirolimus expanded Tregs and CD8+ memory T cells and inhibited IL-4 and IL-17 production by CD4+ and CD4-CD8- double-negative T cells. To validate the results of this recently completed clinical trial and to address critical knowledge gaps in the responsiveness of individual patients, we propose this R34 planning grant to refine the design and infrastructure in support of a multicenter trial to evaluate the safety, efficacy, and mechanism of action by sirolimus. The primary clinical outcome measure will be the difference in SRI. The aims for this application include: 1) Bring together lupus investigators in a multi-center study with a coherent management structure and clear communication strategy; 2) Refine the study protocol for determining the safety and efficacy of sirolimus to ensure a clinically meaningful premise, efficient and affordable trial size, and interpretable results; 3) Standardize clinical assessment techniques to ensure reliability of the primary and secondary outcomes; 4) Design and implement a 21 CRF part 11 compliant electronic data capture system; 5) Establish monitoring procedures for data collection and management; 6) Establish standard procedures for the distribution and handling of study drug from SUNY Pharmacy to each participating center; 7) Adopt standard procedures for blood and urine sample collection and transportation to SUNY Laboratories; 8) Establish compliance with regulatory requirements at each center; 9) Develop protocols for sharing of data and future use of stored biospecimen; 10) Address pitfalls in trial planning; and 11) Finalize the Clinical Protocol, DSMP, CRFs, SOPs, Consent Forms, and Investigators Brochure to meet FDA and OHRP policy requirements as well as the Manual of Operations and Procedures as required by NIAID. The preliminary specific aims for the future clinical trial will be to: 1) Confirm safety and determine efficacy of sirolimus relative to placebo in 184 SLE patients (92 patients per arm, with up to 36 additional subjects to be enrolled for titration of sirolimus to tolerance within a dosage range of 1 to 4 mg/day through an initial 3-month open label period) during a 12-month intervention followed by a 1-month washout; 2) Determine whether mTOR blockade and correction of lineage skewing are sustained over 12 months and predict responsiveness to sirolimus. This study will establish the role of sirolimus as a novel, safe, effective, and biomarker-driven treatment for SLE.